INHIBITION OF RETINOIC ACID RECEPTOR-MEDIATED SIGNALING ALTERS POSITIONAL IDENTITY IN THE DEVELOPING HINDBRAIN

Retinoids regulate gene expression via nuclear retinoic acid receptors , the RARs and RXRs. To investigate the functions of retinoid receptor s during early neural development, we. expressed a dominant negative R AR beta in early Xenopus embryos. We obtained evidence that dominant n egative RAR beta specifically inhibits RAR/RXR heterodimer-mediated, b ut not RXR homodimer-mediated, transactivation. Both all-trans- and 9- cis-RA-induced teratogenesis were, however, efficiently opposed by ect opic expression of dominant negative RAR beta, indicating that only RA R/RXR transactivation is required for retinoid teratogenesis by each o f these ligands. Experiments with two RXR-selective ligands confirmed that activation of RXR homodimers does not cause retinoid teratogenesi s. Dominant negative RAR beta thus specifically interferes with the re tinoid signalling pathway that is responsible for retinoid teratogenes is. Dominant negative RAR beta-expressing embryos had a specific devel opmental phenotype leading to disorganization of the hindbrain. Mauthn er cell multiplications in the posterior hindbrain, and (both anterior ly and posteriorly) expanded Krox-20 expression domains indicated (par tial) transformation of a large part of the hindbrain into (at least p artial) rhombomere 3, 4 and/or 5 identity. In contrast, the fore- and midbrain and spinal cord appeared to be less affected. These data indi cate that RARs play a role in patterning the hindbrain.